Identification of active-site inhibitors of MurG using a generalizable, high-throughput glycosyltransferase screen
Identification of active-site inhibitors of MurG using a generalizable, high-throughput glycosyltransferase screen
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DOI：
10.1021/ja036494s
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发表时间：
2003-09-17
影响因子：
15
通讯作者：
Walker, S
中科院分区：
文献类型：
--
作者：
Helm, JS;Hu, YN;Walker, S
MurG是参与细菌肽聚糖生物合成的糖基转移酶。它是一个潜在的重要抗生素靶点，但尚未报道该酶的抑制剂。通常，糖基转移酶的抑制剂难以设计。此外，还没有通过高通量筛选鉴定出糖基转移酶抑制剂，这可能是因为尚未开发用于糖基转移酶抑制的适当筛选。在这篇手稿中，我们描述了一个高通量筛选MurG的发展，用于筛选50 000化合物库的抑制剂。筛选，这可以推广到其他糖基转移酶，导致识别的一个家庭的活性位点定向MurG抑制剂。抑制剂家族包含一个五元杂环核心，其在取代基的呈现方面似乎起到二磷酸模拟物的作用。我们讨论了这一结果的影响以及筛选用于识别其他糖基转移酶抑制剂的实用性。
MurG is a glycosyltransferase involved in the biosynthesis of bacterial peptidoglycan. It is a potentially important antibiotic target, but no inhibitors of the enzyme have been reported. In general, inhibitors of glycosyltransferases have been difficult to design. Furthermore, no glycosyltransferase inhibitors have been identified through high-throughput screening, perhaps because appropriate screens for glycosyltransferase inhibition have not been developed. In this manuscript, we describe the development of a high-throughput screen for MurG that was used to screen a 50 000 compound library for inhibitors. The screen, which can be generalized to other glycosyltransferases, led to the identification of a family of active-site directed MurG inhibitors. The family of inhibitors contains a five-membered heterocyclic core that appears to function as a diphosphate mimic with respect to the presentation of substituents. We discuss the implications of this result and the utility of the screen for identifying inhibitors of other glycosyltransferases.